Oral care compositions

ABSTRACT

An oral care composition comprising zinc phosphate, stannous fluoride and an organic acid buffer system, as well as methods of using the same.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 16/291,526 (now U.S. Pat. No. 10,709,648), filed on Mar. 4, 2019,which is a continuation application of U.S. Application 15/630,335 (nowU.S. Pat. No. 10,278,906), filed on Jun. 22, 2017 which claims thebenefit and priority of U.S. Provisional Application 62/354,242, filedJun. 24, 2016.

FIELD

The present invention relates to an oral care composition for use in thetreatment or prevention of erosive tooth demineralization, gingivitis,plaque, and dental caries. This oral care composition includes zincphosphate, stannous fluoride, and an organic acid buffer system.

BACKGROUND

Dental erosion involves demineralization and damage to the toothstructure due to acid attack from nonbacterial sources. Erosion is foundinitially in the enamel and, if unchecked, may proceed to the underlyingdentin. Dental erosion may be caused or exacerbated by acidic foods anddrinks, exposure to chlorinated swimming pool water, and regurgitationof gastric acids.

Dental plaque is a sticky biofilm or mass of bacteria that is commonlyfound between the teeth, along the gum line, and below the gum linemargins. Dental plaque can give rise to dental caries and periodontalproblems such as gingivitis and periodontitis. Dental caries tooth decayor tooth demineralization caused by acid produced from the bacterialdegradation of fermentable sugar.

Oral care compositions which contain stannous ion sources exhibitexcellent clinical benefits, particularly in the reduction of gingivitisand in the treatment or prevention of erosive tooth demineralization.Stannous fluoride is well known for use in clinical dentistry with ahistory of therapeutic benefits over forty years. However, untilrecently, its popularity has been limited by its instability in aqueoussolutions. The instability of stannous fluoride in water is primarilydue to the reactivity of the stannous ion (Sn²⁺). Stannous salts readilyhydrolyse above a pH of 4, resulting in precipitation from solution,with a consequent loss of the therapeutic properties.

One way to overcome the stability problems with stannous ions is tolimit the amount of water in the composition to very low levels, or touse a dual phase system. Both of these solutions to the stannous ionproblem have drawbacks. Low water oral care compositions can bedifficult to formulate with desired rheological properties, anddual-phase compositions are considerably more expensive to manufactureand package.

Soluble zinc salts, such as zinc citrate, have been used in dentifricecompositions, but have several disadvantages. Zinc ions in solutionimpart an unpleasant, astringent mouthfeel, so formulations that provideeffective levels of zinc, and also have acceptable organolepticproperties, have been difficult to achieve. Moreover, free zinc ions mayreact with fluoride ions to produce zinc fluoride, which is insolubleand so reduces the availability of both the zinc and the fluoride.Finally, the zinc ions will react with anionic surfactants such assodium lauryl sulfate, thus interfering with foaming and cleaning.

Zinc phosphate (Zn₃(PO₄)₂) is insoluble in water, although soluble inacidic or basic solutions, e.g., solutions of mineral acids, aceticacid, ammonia, or alkali hydroxides. See, e.g., Merck Index, 13^(th) Ed.(2001) p. 1812, monograph number 10205. Partly because it is viewed inthe art as a generally inert material, zinc phosphate is commonly usedin dental cements, for example in cementation of inlays, crowns,bridges, and orthodontic appliances, which are intended to endure in themouth for many years. Zinc phosphate dental cements are generallyprepared by mixing zinc oxide and magnesium oxide powders with a liquidconsisting principally of phosphoric acid, water, and buffers, so thecement comprising zinc phosphate is formed in situ by reaction withphosphoric acid.

Thus, there is a need for providing improved stannous ion containingproducts for treating or preventing erosion of tooth enamel withantimicrobial effectiveness, reducing plaque or treating or controllinggingivitis. There is also a desire for novel anti-microbial compositionsthat are stable in water and easy to manufacture.

BRIEF SUMMARY

Disclosed herein are high water oral care compositions comprising zincphosphate, stannous fluoride, and an organic acid buffer system. Methodsand uses for this composition are also described throughout. Thecompositions disclosed herein provide improved protection fromdemineralization and enhanced antibacterial activity compared to theprior art. In some embodiments, the zinc phosphate is added to thedentifrice as a preformed salt. In some embodiments, the organic acidbuffer system is a citric acid/citrate buffer system. In someembodiments, the oral care composition is a toothpaste or oral gelcomposition.

Further areas of applicability of the present disclosure will becomeapparent from the detailed description provided hereinafter. It shouldbe understood that the detailed description and specific examples, whileindicating the preferred embodiment of the disclosure, are intended forpurposes of illustration only and are not intended to limit the scope ofthe disclosure.

DETAILED DESCRIPTION

The following description of the preferred embodiment(s) is merelyexemplary in nature and is in no way intended to limit the disclosure,its application, or uses.

As used throughout, ranges are used as shorthand for describing each andevery value that is within the range. Any value within the range can beselected as the terminus of the range. In addition, all references citedherein are hereby incorporated by referenced in their entireties. In theevent of a conflict in a definition in the present disclosure and thatof a cited reference, the present disclosure controls.

Unless otherwise specified, all percentages and amounts expressed hereinand elsewhere in the specification should be understood to refer topercentages by weight of the entire composition. The amounts given arebased on the active weight of the material.

It has been surprisingly found that a high water oral care compositioncomprising zinc phosphate, stannous fluoride, and an organic acid buffersystem, selected at certain concentrations and amounts, is unexpectedlymore efficacious in boosting the anti-erosion and anti-microbialproperties of a stannous ions containing formulation when compared toformulations according to the prior art.

As used herein, the term “high water” refers to an oral carecomposition, such as a toothpaste or oral gel, which comprises from 10%to 99% water, by weight of the composition. For example, the compositionmay comprise at least 10%, 15%, 20%, 25%, 30%, 35% or 40% water, up to amaximum of, for example, 60%, 70%, 80%, 90%, 95% or 99% water, by weightof the composition. As used herein, amounts of water refer to wateradded directly to the composition, as well as water added as part ofingredients or components which are added as aqueous solutions. In someembodiments, the composition comprises 10-60% water, or 10-50% water, or10-40% water, or 10-30% water, or 15-30% water, or 20-30% water, orabout 25% water, by weight of the composition.

As used herein, the term “preformed salt”—when used in reference to zincphosphate—means that the zinc phosphate is not formed in situ in theoral care composition, e.g., through the reaction of phosphoric acid andanother zinc salt.

In one aspect, the present disclosure therefore provides a high wateroral care composition (Composition 1) comprising an orally acceptablecarrier, zinc phosphate and stannous fluoride, and an organic acidbuffer system. In further embodiments of this aspect, the presentdisclosure provides:

-   -   1.1 Composition 1, wherein the zinc phosphate is a preformed        salt of zinc phosphate (e.g., zinc phosphate hydrate).    -   1.2 Composition 1 or 1.2, wherein the zinc phosphate is present        in an amount sufficient so that the stannous fluoride        dissociates to provide a therapeutically effective amount of        stannous ions in aqueous solution.    -   1.3 Any preceding composition, wherein the amount of zinc        phosphate is from 0.05 to 10% by weight, relative to the weight        of the oral care composition, for example, from 0.1 to 8% by        weight, or from 0.5 to 5% by weight, or from 0.5 to 4% by        weight, or from 1 to 4%, or from 1 to 3% by weight, or from 2 to        3% by weight, or about 1% or about 2%, or about 2.25% or about        2.5%, by weight.    -   1.4 Any preceding composition, wherein the amount of the        stannous fluoride is from 0.01% to 5% by weight, relative to the        weight of the oral care composition, for example, from 0.05 to        4% by weight, or from 0.1% to 3% by weight, or from 0.2 to 2% by        weight, or from 0.3 to 1% by weight, or from 0.4 to 0.8% by        weight, or from 0.4 to 0.6% by weight, or from 0.4 to 0.5% by        weight, or about 0.45% by weight (e.g., 0.454% by weight).    -   1.5 Any preceding composition, wherein the amount of the water        is 10% by weight or more, relative to the weight of the oral        care composition, for example, 10-90%, or 10-80%, or 10-70%, or        10-60%, or 10-50%, or 10-40%, or 10-30%, or 15-30%, or 20-30%,        or 20-50%, or 30-35%, or about 25% or about 30%, by weight of        the composition.    -   1.6 Any preceding composition, wherein the organic buffer system        comprises a carboxylic acid and one or more conjugate base salts        thereof, for example, alkali metal salts thereof (e.g., citric        acid and sodium citrate).    -   1.7 Composition 1.6, wherein the acid is selected from citric        acid, lactic acid, malic acid, maleic acid, fumaric acid, acetic        acid, succinic acid, and tartaric acid.    -   1.8 Composition 1.6 or 1.7, wherein the one or more conjugate        base salts are independently selected from sodium and potassium        salts, or combinations thereof.    -   1.9 Composition 1.6, 1.7 or 1.8 wherein the acid is citric acid,        and the one or more conjugate base salts comprise monosodium        citrate (monobasic), disodium citrate (dibasic), trisodium        citrate (tribasic), and combinations thereof.    -   1.10 Any preceding composition, wherein the composition        comprises the organic acid buffer system in an amount of 0.1 to        5.0% by weight of the composition, measured as the combined        amount of organic acid and any conjugate base salts; for        example, from 0.5 to 4.0%, or from 1.0 to 3.0%, or from 1.5 to        3.0%, or from 1.0 to 2.4%, or from 1.0% to 2.0%, or from 1.0% to        1.5%, or about 1.2%, by weight of the composition.    -   1.11 Any preceding composition, wherein the buffer system        consists of an organic acid and a conjugate base salt thereof,        for example, in a ratio of from 1:1 to 1:10, e.g., from 1:2 to        1:8, or from 1:3 to 1:6, or from 1:4 to 1:6, or from 1:5 to 1:6,        or about 1:5, by weight of the components.    -   1.12 Any preceding composition, wherein the buffer system        comprises citric acid and a sodium citrate salt (e.g., trisodium        citrate, disodium citrate, or monosodium citrate), in a ratio of        from 1:3 to 1:6, or 1:4 to 1:6, or about 1:5 (e.g., about        1:5.7), by weight.    -   1.13 Any preceding composition, wherein the oral care        composition further comprises an abrasive, for example, silica        abrasives, calcium abrasives, and other abrasives as disclosed        herein.    -   1.14 Any preceding composition, further comprising one or more        humectants, as described herein, e.g., selected from sorbitol,        glycerol, xylitol and propylene glycol, or combinations thereof,        e.g., a combination of sorbitol and glycerin.    -   1.15 Any preceding composition, further comprising one or more        surfactants, as described herein, e.g., sodium lauryl sulfate,        sodium laureth sulfate, or cocamidopropyl betaine, or        combinations thereof, for example, a combination of sodium        lauryl sulfate and cocamidopropyl betaine (e.g., in a combined        amount of 2-5% by weight).    -   1.16 Any preceding composition, further comprising an effective        amount of one or more alkali phosphate salts for example        orthophosphates, pyrophosphates, tripolyphosphates,        tetraphosphates or higher polyphosphates.    -   1.17 Composition 1.16, wherein the alkali phosphate salts        comprise tetrasodium pyrophosphate or tetrapotassium        pyrophosphate, for example, in an amount of 0.5 to 5% by weight        of the composition, e.g., 1-4%, or about 2-4%, or about 1-2% or        about 1.5% or about 2% or about 4%, by weight.    -   1.18 Composition 1.16 or 1.17, wherein the alkali phosphate        salts comprise sodium tripolyphosphate or potassium        tripolyphosphate, for example, in an amount of 0.5 to 6% by        weight of the composition, e.g., 1-4%, or 2-3% or about 3% by        weight.    -   1.19 Any preceding composition, further comprising a whitening        agent.    -   1.20 Any preceding composition, further comprising one or more        sources of zinc ions in addition to the zinc phosphate, for        example a zinc salt selected from zinc citrate, zinc oxide, zinc        lactate, zinc pyrophosphate, zinc sulfate, or zinc chloride.    -   1.21 Any preceding composition, further comprising one or more        fluoride ion sources in addition to the stannous fluoride, for        example, a fluoride ion source selected from sodium fluoride,        potassium fluoride, sodium monofluorophosphate, sodium        fluorosilicate, ammonium fluorosilicate, amine fluoride,        ammonium fluoride, and combinations thereof.    -   1.22 Any preceding composition, wherein the oral care        composition is a dentifrice (e.g., a toothpaste or oral gel),        powder (e.g., tooth powder), cream, strip or gum (e.g., chewing        gum).    -   1.23 Any preceding composition, wherein the pH of the        composition is from 6 to 9, such as from 6.5 to 8, or from 6.5        to 7.5, or about 7.0.    -   1.24 Any preceding composition, wherein the composition is a        single-phase composition (e.g., not a dual-phase composition).    -   1.25 Any preceding composition, wherein the composition does not        comprise one or more of zinc oxide, zinc citrate, or zinc        lactate.    -   1.26 Any preceding composition, wherein the zinc phosphate is        the only zinc ion source.    -   1.27 Any preceding composition, wherein the composition is        essentially free or free of phosphates of more than four        phosphate groups.    -   1.28 Any preceding composition, wherein the composition is        essentially free or free of phosphates of more than three        phosphate groups.    -   1.29 Any preceding composition, wherein the composition is        essentially free or free of hexametaphosphate salts (e.g.,        sodium hexametaphosphate).    -   1.30 Any preceding composition, wherein the composition is free        of methyl vinyl ether-maleic anhydride copolymer.    -   1.31 Any preceding composition, wherein the composition is free        of anionic polymer.    -   1.32 Any of the preceding compositions, wherein the composition        is effective upon application to the oral cavity, e.g., by        rinsing, optionally in conjunction with brushing, to (i) reduce        or inhibit formation of dental caries, (ii) reduce, repair or        inhibit pre-carious lesions of the enamel, e.g., as detected by        quantitative light-induced fluorescence (QLF) or electrical        caries measurement (ECM), (iii) reduce or inhibit        demineralization and promote remineralization of the teeth, (iv)        reduce hypersensitivity of the teeth, (v) reduce or inhibit        gingivitis, (vi) promote healing of sores or cuts in the        mouth, (vii) reduce levels of acid producing bacteria, (viii) to        increase relative levels of arginolytic bacteria, (ix) inhibit        microbial biofilm formation in the oral cavity, (x) raise and/or        maintain plaque pH at levels of at least pH 5.5 following sugar        challenge, (xi) reduce plaque accumulation, (xii) treat, relieve        or reduce dry mouth, (xiii) clean the teeth and oral        cavity (xiv) reduce erosion, (xv) prevents stains and/or whiten        teeth, (xvi) immunize the teeth against cariogenic bacteria;        and/or (xvii) promote systemic health, including cardiovascular        health, e.g., by reducing potential for systemic infection via        the oral tissues.    -   1.33 Any preceding compositions, wherein the composition further        comprises a polymer selected from carboxymethyl cellulose (free        form or a salt, e.g., sodium salt), a gum (e.g., xanthan gum,        carrageenan gum, or gum arabic), polyethylene glycol (e.g.,        polyethylene glycol 200, 400, 600 or 800, or a mixture thereof),        and a mixture thereof, for example, a mixture of sodium carboxy        methyl cellulose, xanthan gum and polyethylene glycol 600.    -   1.34 Any preceding composition further comprising a silica        thickener and/or a silica abrasive.    -   1.35 Any preceding composition comprising the following        ingredients:

Zinc phosphate 0.05-2.5%, e.g., about 1% (e.g., zinc phosphate hydrate)Stannous fluoride 0.3-1%, e.g., about 0.45% Alkali metal pyrophosphate1-5%, e.g., about 2% or 4% (e.g., tetrasodium or tetrapotassiumpyrophosphate) Sodium citrate, e.g., trisodium 0.8-2.5%, e.g., about 1%citrate dihydrate Citric acid 0.15-0.5%, e.g., about 0.2% AnionicSurfactant 1-3%, e.g., about 1.5% (e.g., sodium lauryl sulfate)Zwitterionic Surfactant 1-3%, e.g., about 1.25% (e.g., CAPB) Sorbitol20-50%, e.g., about 40% (e.g., 70 wt % sorbitol) Glycerin 1-8%, e.g.,about 4% Gum polymer 0.05-2%, e.g., about 0.3% (e.g., xanthan gum)Polyethylene glycol 1-5%, e.g., about 2% (e.g., PEG 600) Carboxymethylcellulose 0.5-3%, e.g., about 2% (e.g., Sodium CMC) Water 10-30%, e.g.,15-20%, e.g., (e.g., added water) about 20% Total Water 20-50%, e.g.,about 30%

Any amount of zinc phosphate that is effective for protecting againstenamel erosion and/or providing any of the other benefits describedherein can be employed. Examples of suitable amounts of zinc phosphatecan range from 0.05 to 5% by weight, such as from 0.1 to 4% by weight,or from 0.5 to 3% by weight, or from 0.5 to 2% by weight, or from 0.8 to1.5% by weight, or from 0.9 to 1.1% by weight, or about 1% by weight,relative to the weight of the oral care composition.

While zinc phosphate is considered insoluble (e.g., poorly soluble), inwater, when placed in formulation, e.g., at acidic or basic pH, zincphosphate can dissolve sufficiently upon use to provide an effectiveconcentration of zinc ions to the enamel, thereby protecting againsterosion, reducing bacterial colonization and biofilm development, andproviding enhanced shine to the teeth. It has also been discovered thatzinc phosphate in a formulation with a second phosphate source enhancesphosphate deposition. As explained in WO2014/088573, the disclosure ofwhich is hereby incorporated by reference in its entirety, this is allunexpected, in view of the poor solubility of zinc phosphate, and theart-recognized view that it is substantially inert in conditions in theoral cavity, as evidenced by its widespread use in dental cement. At thesame time, the formulations containing zinc phosphate do not exhibit thepoor taste and mouthfeel, poor fluoride delivery, and poor foaming andcleaning associated with conventional zinc-based oral care products,which use more soluble zinc salts.

An amount of stannous fluoride, preferably an effective amount, isemployed in combination with the zinc phosphate in the compositions ofthe present disclosure. For example, the stannous fluoride can beemployed in an amount that is effective for providing anti-microbialbenefits, such as anti-caries protection and/or anti-gingivitisprotection, and/or anti-erosion benefits for protection of tooth enamel.Examples of suitable amounts of stannous fluoride range from 0.01% to 5%by weight, relative to the weight of the oral care composition, forexample, from 0.05 to 4% by weight, or from 0.1% to 3% by weight, orfrom 0.2 to 2% by weight, or from 0.3 to 1% by weight, or from 0.4 to0.8% by weight, or from 0.4 to 0.6% by weight, or from 0.4 to 0.5% byweight, or about 0.45% by weight (e.g., 0.454%), relative to the totalweight of the dentifrice composition. Formulations can include stannouslevels, provided by stannous fluoride, ranging for example, from 3,000ppm to 15,000 ppm (mass fraction) stannous ions in the totalcomposition. In embodiments, the soluble stannous content can range from0.1 wt % to 0.5 wt %, or more, such as from 0.15 wt % to 0.32 wt %,based on the total weight of the composition.

The combination of zinc and stannous ions provides one or more of thefollowing benefits: improved antimicrobial benefits compared to the zincions alone; improved control of plaque and/or gingivitis; improvedprotection against the erosion of tooth enamel.

In compositions comprising significant amounts of water, the zincphosphate acts as a stabilizing agent for the stannous fluoride, so thatthe stannous fluoride remains in solution in the water. As discussedabove, stannous fluoride is generally considered unstable in water dueto the hydrolytic and oxidative loss of stannous ions at typical pHranges employed in oral care compositions. Consequently, stannousfluoride is generally employed in compositions containing no water orlow water, or with a chelating agent. Tedious procedures are employed inorder to provide stable solutions in which the tendency of the stannousion to be oxidized or hydrolyzed is inhibited. Applicants havesurprisingly found that zinc phosphate and stannous fluoride can becombined together in a single phase formulation and stabilized by thepresence of an appropriate organic acid buffer system. The organic acidbuffer system helps solubilize the zinc phosphate and it helps stabilizethe soluble stannous ions.

The compositions may optionally comprise additional ingredients suitablefor use in oral care compositions. Examples of such ingredients includeactive agents, such as a fluoride source and/or a phosphate source inaddition to zinc phosphate. The compositions may be formulated in asuitable dentifrice base, e.g., comprising abrasives, e.g., silicaabrasives, surfactants, foaming agents, vitamins, polymers, enzymes,humectants, thickeners, additional antimicrobial agents, preservatives,flavorings, colorings, and/or combinations thereof. Examples of suitabledentifrice bases are known in the art. Alternatively, the compositionsmay be formulated as a gel (e.g., for use in a tray), chewing gum,lozenge or mint. Examples of suitable additional ingredients that can beemployed in the compositions of the present disclosure are discussed inmore detail below.

Active Agents: The compositions of the disclosure may comprise variousother agents that are active to protect and enhance the strength andintegrity of the enamel and tooth structure and/or to reduce bacteriaand associated tooth decay and/or gum disease or to provide otherdesired benefits. Effective concentration of the active ingredients usedherein will depend on the particular agent and the delivery system used.The concentration will also depend on the exact salt or polymerselected. For example, where the active agent is provided in salt form,the counterion will affect the weight of the salt, so that if thecounterion is heavier, more salt by weight will be required to providethe same concentration of active ion in the final product.

Compositions of the disclosure may contain from 0.1 to 1 wt % of anantibacterial agent, such as about 0.3 wt. %. Any suitable antimicrobialactives can be employed.

Fluoride Ion Source: The oral care compositions can include one or moreadditional fluoride ion sources, e.g., soluble fluoride salts. A widevariety of fluoride ion-yielding materials can be employed as sources ofsoluble fluoride in the present compositions. Examples of suitablefluoride ion-yielding materials are found in U.S. Pat. No. 3,535,421, toBriner et al.; U.S. Pat. No. 4,885,155, to Parran, Jr. et al. and U.S.Pat. No. 3,678,154, to Widder et al, the disclosure of each of which ishereby incorporated by reference in their entirety. Representativefluoride ion sources include, but are not limited to, sodium fluoride,potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate,ammonium fluorosilicate, amine fluoride, ammonium fluoride, andcombinations thereof. In certain embodiments the fluoride ion sourceincludes sodium fluoride, sodium monofluorophosphate as well as mixturesthereof. In certain embodiments, the oral care composition of thedisclosure may contain stannous fluoride and any additional source offluoride ions or fluorine-providing agents in amounts sufficient tosupply, in total, from 25 ppm to 25,000 ppm (mass fraction) of fluorideions, generally at least 500 ppm, e.g., from 500 to 2000 ppm, e.g., from1000 to 1600 ppm, e.g., about 1450 ppm. The appropriate level offluoride will depend on the particular application. A toothpaste forgeneral consumer use would typically have from1000 to about 1500 ppm,with pediatric toothpaste having somewhat less. A dentifrice or coatingfor professional application could have as much as 5,000 or even about25,000 ppm fluoride. Additional fluoride ion sources may be added to thecompositions of the disclosure at a level of from 0.01 wt. % to 10 wt. %in one embodiment or from 0.03 wt. % to 5 wt. %, and in anotherembodiment from 0.1 wt. % to 1 wt. % by weight of the composition. Asdiscussed above, weights of fluoride salts to provide the appropriatelevel of fluoride ion will vary based on the weight of the counterion inthe salt.

Abrasives: The compositions of the disclosure can include abrasives.Examples of suitable abrasives include silica abrasives, such asstandard cleaning silicas, high cleaning silicas or any other suitableabrasive silicas. Additional examples of abrasives that can be used inaddition to or in place of the silica abrasives include, for example, acalcium phosphate abrasive, e.g., tricalcium phosphate (Ca₃(PO₄)₂),hydroxyapatite (Ca_(io)(PO₄)₆(OH)₂), or dicalcium phosphate dihydrate(CaHPO₄.2H₂O, also sometimes referred to herein as DiCal) or calciumpyrophosphate; calcium carbonate abrasive; or abrasives such as sodiummetaphosphate, potassium metaphosphate, aluminum silicate, calcinedalumina, bentonite or other siliceous materials, or combinationsthereof.

Silica abrasive polishing materials useful herein, as well as the otherabrasives, generally have an average particle size ranging between 0.1and 30 microns, such as between 5 and 15 microns. The silica abrasivescan be from precipitated silica or silica gels, such as the silicaxerogels described in U.S. Pat. No. 3,538,230, to Pader et al. and U.S.Pat. No. 3,862,307, to Digiulio, the disclosures of which areincorporated herein by reference in their entireties. Particular silicaxerogels are marketed under the trade name Syloid® by the W. R. Grace &Co., Davison Chemical Division. The precipitated silica materialsinclude those marketed by the J. M. Huber Corp. under the trade nameZeodent®, including the silica carrying the designation Zeodent 115 and119. These silica abrasives are described in U.S. Pat. No. 4,340,583, toWason, the disclosure of which is incorporated herein by reference inits entirety. In certain embodiments, abrasive materials useful in thepractice of the oral care compositions in accordance with the disclosureinclude silica gels and precipitated amorphous silica having an oilabsorption value of less than 100 cc/100 g silica, such as from 45cc/100 g to 70 cc/100 g silica. Oil absorption values are measured usingthe ASTA Rub-Out Method D281. In certain embodiments, the silicas arecolloidal particles having an average particle size of from 3 microns to12 microns, and from 5 to 10 microns. Examples of low oil absorptionsilica abrasives useful in the practice of the disclosure are marketedunder the trade designation Sylodent XWA® by Davison Chemical Divisionof W. R. Grace & Co., Baltimore, Md. 21203. Sylodent 650 XWA®, a silicahydrogel composed of particles of colloidal silica having a watercontent of 29% by weight averaging from 7 to 10 microns in diameter, andan oil absorption of less than 70 cc/100 g of silica is an example of alow oil absorption silica abrasive useful in the practice of the presentdisclosure.

Any suitable amount of silica abrasive can be employed. Examples ofsuitable amounts include 10 wt. % or more dry weight of silicaparticles, such as from 15 wt. % to 30 wt. % or from 15 wt. % to 25 wt.%, based on the total weight of the composition.

Foaming agents: The oral care compositions of the disclosure also mayinclude an agent to increase the amount of foam that is produced whenthe oral cavity is brushed. Illustrative examples of agents thatincrease the amount of foam include, but are not limited topolyoxyethylene and certain polymers including, but not limited to,alginate polymers. The polyoxyethylene may increase the amount of foamand the thickness of the foam generated by the oral care compositions ofthe present disclosure. Polyoxyethylene is also commonly known aspolyethylene glycol (“PEG”) or polyethylene oxide. The polyoxyethylenessuitable for compositions of the present disclosure may have a molecularweight of from 200,000 to 7,000,000. In one embodiment the molecularweight may be from 600,000 to 2,000,000 and in another embodiment from800,000 to 1,000,000. Polyox® is the trade name for the high molecularweight polyoxyethylene produced by Union Carbide. The foaming agent,(e.g., polyoxyethylene) may be present in an amount of from 0.1% to 50%,in one embodiment from 0.5% to 20% and in another embodiment from 1% to10%, or from 2% to 5% by weight of the oral care compositions of thepresent disclosure.

Surfactants: The compositions useful in the compositions of the presentdisclosure may contain anionic surfactants, for example:

-   -   i. water-soluble salts of higher fatty acid monoglyceride        monosulfates, such as the sodium salt of the monosulfated        monoglyceride of hydrogenated coconut oil fatty acids such as        sodium N-methyl N-cocoyl taurate, sodium cocomonoglyceride        sulfate,    -   ii. higher alkyl sulfates, such as sodium lauryl sulfate,    -   iii. higher alkyl-ether sulfates, e.g., of formula        CH₃(CH₂)_(m)CH₂(OCH₂CH₂)_(n)OSO₃X, wherein m is 6-16, e.g., 10,        n is 1-6, e.g., 2, 3 or 4, and X is Na or K, for example sodium        laureth-2 sulfate (CH₃(CH₂)₁₀CH₂(OCH₂CH₂)₂OSO₃Na),    -   iv. higher alkyl aryl sulfonates such as sodium dodecyl benzene        sulfonate (sodium lauryl benzene sulfonate),    -   v. higher alkyl sulfoacetates, such as sodium lauryl        sulfoacetate (dodecyl sodium sulfoacetate), higher fatty acid        esters of 1,2 dihydroxy propane sulfonate, sulfocolaurate        (N-2-ethyl laurate potassium sulfoacetamide) and sodium lauryl        sarcosinate.

By “higher alkyl” is meant, e.g., C₆₋₃₀ alkyl. In certain embodiments,the anionic surfactants useful herein include the water-soluble salts ofalkyl sulfates having from 10 to 18 carbon atoms in the alkyl radicaland the water-soluble salts of sulfonated monoglycerides of fatty acidshaving from 10 to 18 carbon atoms. Sodium lauryl sulfate, sodium lauroylsarcosinate and sodium coconut monoglyceride sulfonates are examples ofanionic surfactants of this type. In particular embodiments, the anionicsurfactant is selected from sodium lauryl sulfate and sodium etherlauryl sulfate. In a particular embodiment, the compositions of thedisclosure comprise sodium lauryl sulfate. The anionic surfactant may bepresent in an amount which is effective, e.g., >0.01% by weight of theformulation, but not at a concentration which would be irritating to theoral tissue, e.g., <10%, and optimal concentrations depend on theparticular formulation and the particular surfactant. In one embodiment,the anionic surfactant is present in a toothpaste at from 0.3% to 4.5%by weight, e.g., about 1.5%. The compositions of the disclosure mayoptionally contain mixtures of surfactants, e.g., comprising anionicsurfactants and other surfactants that may be anionic, cationic,zwitterionic or nonionic. Generally, suitable surfactants are thosewhich are reasonably stable throughout a wide pH range. Surfactants aredescribed more fully, for example, in U.S. Pat. No. 3,959,458, toAgricola et al.; U.S. Pat. No. 3,937,807, to Haefele; and U.S. Pat. No.4,051,234, to Gieske et al, the disclosures of which are incorporatedherein by reference in their entireties.

The surfactant or mixtures of compatible surfactants that are includedin addition to the anionic surfactants can be present in thecompositions of the present disclosure in from 0.1% to 5.0%, in anotherembodiment from 0.3% to 3.0% and in another embodiment from 0.5% to 2.0%by weight of the total composition. These ranges do not include theanionic surfactant amounts.

In some embodiments, the compositions of the present disclosure includea zwitterionic surfactant, for example a betaine surfactant, for examplecocamidopropylbetaine, e.g. in an amount of from 0.1% to 4.5% by weight,e.g. from 0.5 to 2% by weight cocamidopropylbetaine.

Tartar control agents: In various embodiments of the present disclosure,the compositions comprise an anticalculus (tartar control) agent.Suitable anticalculus agents include, without limitation, phosphates andpolyphosphates (for example pyrophosphates and tripolyphosphates),polyaminopropanesulfonic acid (AMPS), hexametaphosphate salts, zinccitrate trihydrate, polypeptides, polyolefin sulfonates, polyolefinphosphates, and diphosphonates. The compositions of the disclosure thusmay comprise phosphate salts in addition to the zinc phosphate. Inparticular embodiments, these salts are alkali phosphate salts, e.g.,salts of alkali metal hydroxides or alkaline earth hydroxides, forexample, sodium, potassium or calcium salts. “Phosphate” as used hereinencompasses orally acceptable mono- and polyphosphates, for example,P₁₋₆ phosphates, for example monomeric phosphates such as monobasic,dibasic or tribasic phosphate; and dimeric phosphates such aspyrophosphates; and multimeric phosphates, such as tripolyphosphates,tetraphosphates, hexaphosphates and hexametaphosphates (e.g., sodiumhexametaphosphate). In particular examples, the selected phosphate isselected from alkali dibasic phosphate and alkali pyrophosphate salts,e.g., selected from sodium phosphate dibasic, potassium phosphatedibasic, dicalcium phosphate dihydrate, calcium pyrophosphate,tetrasodium pyrophosphate, tetrapotassium pyrophosphate, sodiumtripolyphosphate, and mixtures of any of two or more of these. In aparticular embodiment, for example the compositions may comprisetetrasodium pyrophosphate in an amount of from 0.5 to 5% by weight,e.g., 1-3%, or 1-4%, or 2-4%, or 1-2% or about 2%, or about 4% by weightof the composition. In another embodiment, the compositions may comprisea mixture of tetrasodium pyrophosphate (TSPP) and sodiumtripolyphosphate (STPP), e.g., in proportions of TSPP at from 0.5 to 5wt. %, such as from 1 to 2 wt. % or 1 to 4 wt. % and STPP at from 0.5%to 6 wt. %, such as 1 to 4%, or 2 to 3% by weight of the composition.Such phosphates are provided in an amount effective to reduce erosion ofthe enamel, to aid in cleaning the teeth, and/or to reduce tartarbuildup on the teeth, for example in an amount of from 0.2 to 20 wt. %,e.g., from 1 to 15 wt. %, by weight of the composition.

Flavoring Agents: The oral care compositions of the disclosure may alsoinclude a flavoring agent. Flavoring agents which are used in thepractice of the present disclosure include, but are not limited to,essential oils as well as various flavoring aldehydes, esters, alcohols,and similar materials. Examples of the essential oils include oils ofspearmint, peppermint, wintergreen, sassafras, clove, sage, eucalyptus,marjoram, cinnamon, lemon, lime, grapefruit, and orange. Also useful aresuch chemicals as menthol, carvone, and anethole. Certain embodimentsemploy the oils of peppermint and spearmint. The flavoring agent may beincorporated in the oral composition at a concentration of from 0.1 to5% by weight e.g., from 0.5 to 1.5% by weight.

Polymers: The oral care compositions of the disclosure may also includeadditional polymers to adjust the viscosity of the formulation orenhance the solubility of other ingredients. Such additional polymersinclude polyethylene glycols, polysaccharides (e.g., cellulosederivatives, for example carboxymethyl cellulose, hydroxymethylcellulose, ethyl cellulose, microcrystalline cellulose or polysaccharidegums, for example xanthan gum, guar gum or carrageenan gum). Acidicpolymers, for example polyacrylate gels, may be provided in the form oftheir free acids or partially or fully neutralized water soluble alkalimetal (e.g., potassium and sodium) or ammonium salts. In one embodiment,the oral care composition may contain PVP. PVP generally refers to apolymer containing vinylpyrrolidone (also referred to asN-vinylpyrrolidone, N-vinyl-2-pyrrolidone and N-vinyl-2-pyrrolidinone)as a monomeric unit. The monomeric unit consists of a polar imide group,four non-polar methylene groups and a non-polar methane group.

In some embodiments, the compositions of the disclosure comprise one ormore polyethylene glycols, for example, polyethylene glycols in amolecular weight range from 200 to 800. For example, the compositionsmay comprise one or more of polyethylene glycol 200, polyethylene glycol300, polyethylene glycol 400, polyethylene glycol, 600 or polyethyleneglycol 800.

Silica thickeners, which form polymeric structures or gels in aqueousmedia, may be present. Note that these silica thickeners are physicallyand functionally distinct from the particulate silica abrasives alsopresent in the compositions, as the silica thickeners are very finelydivided and provide little or no abrasive action. Other thickeningagents are carboxyvinyl polymers, carrageenan, hydroxyethyl celluloseand water soluble salts of cellulose ethers such as sodium carboxymethylcellulose and sodium carboxymethyl hydroxyethyl cellulose. Natural gumssuch as karaya, gum arabic, and gum tragacanth can also be incorporated.Colloidal magnesium aluminum silicate can also be used as component ofthe thickening composition to further improve the composition's texture.In certain embodiments, thickening agents in an amount of from 0.5% to5.0% by weight of the total composition are used.

In some embodiments, the compositions of the disclosure may include ananionic polymer, for example in an amount of from 0.05 to 5%. Examplesof such agents generally known for use in dentifrice are disclosed inU.S. Pat. Nos. 5,188,821 and 5,192,531, both of which are incorporatedherein by reference in their entirety; and include synthetic anionicpolymeric polycarboxylates, such as 1:4 to 4:1 copolymers of maleicanhydride or acid with another polymerizable ethylenically unsaturatedmonomer, preferably methyl vinyl ether/maleic anhydride having amolecular weight (M. W.) of from 30,000 to 1,000,000, such as from300,000 to 800,000. These copolymers are available for example asGantrez, e.g., AN 139 (M. W. 500,000), AN 119 (M. W. 250,000) andpreferably S-97 Pharmaceutical Grade (M. W. 700,000) available from ISPTechnologies, Inc., Bound Brook, N.J. 08805. The enhancing agents whenpresent are present in amounts ranging from 0.05 to 3% by weight. Otheroperative polymers include those such as the 1:1 copolymers of maleicanhydride with ethyl acrylate, hydroxyethyl methacrylate,N-vinyl-2-pyrrolidone, or ethylene, the latter being available forexample as Monsanto EMA No. 1103, M. W. 10,000 and EMA Grade 61, and 1:1copolymers of acrylic acid with methyl or hydroxyethyl methacrylate,methyl or ethyl acrylate, isobutyl vinyl ether or N-vinyl-2-pyrrolidone.Suitable generally, are polymerized olefinically or ethylenicallyunsaturated carboxylic acids containing an activated carbon-to-carbonolefinic double bond and at least one carboxyl group, that is, an acidcontaining an olefinic double bond which readily functions inpolymerization because of its presence in the monomer molecule either inthe alpha-beta position with respect to a carboxyl group or as part of aterminal methylene grouping. Illustrative of such acids are acrylic,methacrylic, ethacrylic, alpha-chloroacrylic, crotonic, beta-acryloxypropionic, sorbic, alpha-chlorsorbic, cinnamic, beta-styrylacrylic,muconic, itaconic, citraconic, mesaconic, glutaconic, aconitic,alpha-phenylacrylic, 2-benzyl acrylic, 2-cyclohexylacrylic, angelic,umbellic, fumaric, maleic acids and anhydrides. Other different olefinicmonomers copolymerizable with such carboxylic monomers includevinylacetate, vinyl chloride, dimethyl maleate and the like. Copolymerscontain sufficient carboxylic salt groups for water-solubility. Afurther class of polymeric agents includes a composition containinghomopolymers of substituted acrylamides and/or homopolymers ofunsaturated sulfonic acids and salts thereof, in particular wherepolymers are based on unsaturated sulfonic acids selected fromacrylamidoalykane sulfonic acids such as 2-acrylamide 2-methylpropanesulfonic acid having a molecular weight of from 1,000 to 2,000,000.Another useful class of polymeric agents includes polyamino acidscontaining proportions of anionic surface-active amino acids such asaspartic acid, glutamic acid and phosphoserine, e.g. as disclosed inU.S. Pat. No. 4,866,161, issued to Sikes et al., which is alsoincorporated herein by reference in its entirety.

In some embodiments, there are no anionic polymers present in thecomposition. In other embodiments, there may be anionic polymerspresent, but they do not include copolymers of methyl vinyl ether andmaleic acid or anhydride.

Humectants: Within certain embodiments of the oral compositions, it isalso desirable to incorporate a humectant to prevent the compositionfrom hardening upon exposure to air. Certain humectants can also impartdesirable sweetness or flavor to dentifrice compositions. Suitablehumectants include edible polyhydric alcohols such as glycerin,sorbitol, xylitol, propylene glycol as well as other polyols andmixtures of these humectants. In one embodiment of the disclosure, theprincipal humectant is one of glycerin, sorbitol or a combinationthereof. The humectant may be present at levels of greater than 15 wt.%, such as from 15 wt. % to 55 wt. %, or from 20 wt. % to 50 wt. %, orfrom 20 wt. % to 40 wt. %, or about 20% or about 30% or about 40%, basedon the total weight of the composition.

Other optional ingredients: In addition to the above-describedcomponents, the embodiments of this disclosure can contain a variety ofoptional oral care ingredients some of which are described below.Optional ingredients include, for example, but are not limited to,adhesives, sudsing agents, flavoring agents, sweetening agents such assodium saccharin, additional antiplaque agents, abrasives, aestheticssuch as TiO₂ coated mica or other coloring agents, such as dyes and/orpigments.

In some embodiments, the compositions of the present disclosure can haveany pH suitable for in a product for use in oral care. Examples ofsuitable pH ranges are from 6 to 9, such as from 6.5 to 8, or 6.5 to7.5, or about 7.0.

In some embodiments, the oral care compositions of the presentdisclosure are either essentially free of, free of, or do not includeany sodium hexametaphosphate. In some embodiments, the oral carecompositions of the present disclosure are either essentially free of,free of, or do not include any halogenated diphenyl ethers (e.g.,triclosan).

By “essentially free” is meant that the compositions have no more than0.01% by weight of these compounds.

In some embodiments, the compositions of the present disclosure areeither essentially free of, free of or do not include any complexingagents for increasing solubility of zinc phosphate and/or formaintaining the stannous fluoride in solution. Examples of knowncomplexing agents that can be excluded from the compositions of thepresent disclosure include the chelating agents taught in U.S. PatentApplication No. 2007/0025928, the disclosure of which is herebyincorporated by reference in its entirety. Such chelating agents includemineral surface-active agents, including mineral surface-active agentsthat are polymeric and/or polyelectrolytes and that are selected fromphosphorylated polymers, wherein if the phosphorylated polymer is apolyphosphate, the polyphosphate has average chain length of 3.5 ormore, such as 4 or more; polyphosphonates; polycarboxylates;carboxy-substituted polymers; copolymers of phosphate- orphosphonate-containing monomers or polymers with ethylenicallyunsaturated monomers, amino acids, proteins, polypeptides,polysaccharides, poly(acrylate), poly(acrylamide), poly(methacrylate),poly(ethacrylate), poly(hydroxyalkylmethacrylate), poly(vinyl alcohol),poly(maleic anhydride), poly(maleate) poly(amide), poly(ethylene amine),poly(ethylene glycol), poly(propylene glycol), poly(vinyl acetate) andpoly(vinyl benzyl chloride); and mixtures thereof. Other knowncomplexing agents that can be excluded from the compositions of thepresent disclosure include those taught in CA 2634758, the disclosure ofwhich is incorporated here by reference in its entirety. Examplesinclude polyphosphorylated inositol compounds such as phytic acid,myo-inositol pentakis(dihydrogen phosphate); myo-inositoltetrakis(dihydrogen phosphate), myo-inositol trikis(dihydrogenphosphate), and alkali metal, alkaline earth metal or ammonium salts ofany of the above inositol compounds. Phytic acid is also known asmyo-inositol 1,2,3,4,5,6-hexakis (dihydrogen phosphate) or inositolhexaphosphoric acid.

In another aspect, the present disclosure provides a method of treatmentor prevention of erosive tooth demineralization, gingivitis, plaque,and/or dental caries, the method comprising the application to the oralcavity of a person in need thereof a composition according to theinvention (e.g., Composition 1.0 et seq), e.g., by brushing, forexample, one or more times per day.

In another aspect, the present disclosure provides a method of using thecompositions described herein (e.g., any of Compositions 1.0 et seq) toincrease zinc levels in the enamel and to treat, reduce or control theincidence of enamel erosion. The methods comprise applying any of thecompositions as described herein to the teeth, e.g., by brushing, orotherwise administering the compositions to the oral cavity of a subjectin need thereof. The compositions can be administered regularly, suchas, for example, one or more times per day. In various embodiments,administering the compositions of the present disclosure to a patientcan provide one or more of the following benefits: (i) reducehypersensitivity of the teeth, (ii) reduce plaque accumulation, (iii)reduce or inhibit demineralization and promote remineralization of theteeth, (iv) inhibit microbial biofilm formation in the oral cavity, (v)reduce or inhibit gingivitis, (vi) promote healing of sores or cuts inthe mouth, (vii) reduce levels of acid producing bacteria, (viii)increase relative levels of non-cariogenic and/or non-plaque formingbacteria, (ix) reduce or inhibit formation of dental caries, (x) reduce,repair or inhibit pre-carious lesions of the enamel, e.g., as detectedby quantitative light-induced fluorescence (QLF) or electrical cariesmeasurement (ECM), (xi) treat, relieve or reduce dry mouth, (xii) cleanthe teeth and oral cavity, (xiii) reduce erosion, (xiv) whiten teeth;(xv) reduce tartar build-up, and/or (xvi) promote systemic health,including cardiovascular health, e.g., by reducing potential forsystemic infection via the oral tissues. The disclosure further providescompositions for use in any of the above methods. Further embodimentsprovide methods wherein at least one tooth is remineralized afteradministration of a composition as described herein.

The present application further discloses a method of making any of thecompositions of the present disclosure. The method comprises combiningzinc phosphate and stannous fluoride in water to form an aqueous zincphosphate mixture. In some embodiments, the zinc phosphate is added tothe dentifrice composition as a preformed salt and remains essentiallyinsoluble in the aqueous mixture. The amount of water employed in themixture can be any of the amounts recited herein for the compositions ofthe present disclosure. Any standard mixing techniques can be employedto combine the ingredients and form a stable composition without theneed for additional complexing agents to solubilize the stannousfluoride, such as any of the above disclosed complexing or chelatingagents, or the use of anhydrous mixing techniques such as dissolvingstannous fluoride in an anhydrous material such as glycerin.

EXAMPLES Example 1 Dentifrice Formulation

Representative Dentifrice Formulations according to the presentdisclosure are prepared according to Table 1 below:

TABLE 1 Ingredient Weight % Water Q.S. (e.g. 15-40) Humectants 15-55(e.g. 40) Abrasives 10-30 (e.g. 20) Thickeners 0.5-5 (e.g. 3.6) OrganicAcid Buffer Salt 0.0-0.6 (e.g., TrisodiumCitrate) Zinc Phosphate 0.05-5(e.g. 2.3) Flavor, Sweetener, Colors 0.5-5 (e.g. 0.65) Alkali PhosphateSalts 0.5-5 (e.g. 2) Anionic Surfactant 0.01-10 (e.g. 1.50) ZwitterionicSurfactant 0.1-4.5 (e.g. 1.25) Organic Acid Buffer Acid 0.0-3.0 (e.g.Citric Acid) Stannous Fluoride 0.5-11 (e.g. 0.454)

Experimental dentifrice compositions are prepared based on the baseformulation shown in Table 2. Each dentifrice comprises 0.454% stannousfluoride and 2.35% zinc phosphate hydrate, but varies in theconcentration of citric acid and trisodium citrate dihydrate present.Ingredients in Table 1 are listed by weight of the composition.

TABLE 2 Ingredient Weight % Water Q.S. (e.g. 15-25%) Humectants(Sorbitol, Glycerin, Propylene 40 Glycol, Polyethylene Glycol) Abrasives20 Thickeners 3.6 Trisodium Citrate, Dihydrate 0.0-0.6 Zinc Phosphate2.3 Flavor, Sweetener, Colors 0.65 Tetrasodium Pyrophosphate 2.0 AnionicSurfactant 1.50 Zwitterionic Surfactant 1.25 Citric Acid- Anhydrous0.0-3.0 Stannous Fluoride 0.454

Example 2 Stannous and Zinc Solubility and Uptake

Seven variations of the base formulation shown in Table 2 are prepared.To measure metal ion solubility, slurries of each test dentifrice indeionized water are prepared at a 10% w/v dilution. The slurries arestirred vigorously for 30 minutes, and then filtered to remove insolublematerial. The recovered filtrates are analyzed for soluble stannous ion,soluble zinc ion, and soluble fluoride ion by atomic absorptionspectroscopy. Results for stannous and zinc are presented as aproportion of the respective ion present in the neat formulation (%).Results for fluoride are presented as ppm. pH is measured as the 10% w/vaqueous suspension.

Metal ion uptake is measured using the Vitro-Skin soft tissue protocol.Vitro-Skin (IMS Inc., Portland, Me.) is cut into uniform circles of20-21 mm diameter, and the circles are rinsed in bulk with hexane andair dried to remove the silicone coating. After soaking the circles insterilized, clear human saliva for three hours, the saliva is removedand the Vitro-Skin circles are added to a fresh slurry of the testcomposition in water (1 mL of slurry formed from 2.0 g composition plus4 mL water). After incubating for 10 minutes at 37° C., the slurry isremoved and the Vitro-skin circles are rinsed three times with distilledwater. The circles are then soaked overnight in 1 mL of concentratednitric acid. After dilution to a volume of 10 mL with distilled water,the resulting mixture is analyzed for stannous and zinc concentration byatomic absorption spectroscopy. Uptake is measured in units of microgramper square centimeter based on both sides of the Vitro-Skin circletested. The results are shown in Table 3 below.

TABLE 3 Buffer System (wt %) Solubility Uptake Test Sodium Citric (F:ppm; Sn/Zn: %) (μg/cm²) Comp. Citrate* Acid F Sn Zn Sn Zn pH 1 0.00 0.001095 0.12 0.20 1.32 1.66 7.70 2 0.09 0.50 1097 0.20 0.21 1.52 2.43 7.763 0.18 1.00 1097 0.25 0.28 2.12 4.13 7.56 4 0.26 1.50 1112 0.30 0.352.30 3.07 7.46 5 0.35 2.00 1075 0.33 0.43 2.00 4.78 7.32 6 0.44 2.501070 0.39 0.49 1.73 4.71 7.08 7 0.53 3.00 1086 0.41 0.57 2.34 3.60 7.05*Sodium citrate added as the dihydrate salt (87.8 wt % sodium citrate)

The data shows that the addition of a buffer system comprising 5:1 byweight of citric acid/trisodium citrate dihydrate (5.68:1 by weightcitric acid/trisodium citrate anhydrous), the amount of soluble stannousand zinc is substantially increased, without a loss in fluoridesolubility. The results show a steady increase in metal ion solubilityas the concentration of the buffer system in the dentifrice is raised.Metal ion uptake is similarly increased, with optimum uptake occurringat about 1.76 to 2.94 wt % buffer system.

Example 3 Antibacterial Efficacy

Anti-bacterial efficacy is measured using an ATP bioluminescence assaywith planktonic bacteria (BacTiter-Glo Microbial Cell Viability Assay,from Promega). Assays are performed at both a 1:4 dilution and a 1:8dilution of the dentifrice in phosphate-buffered saline. Compositions 1,2, 4 and 7 are compared to a commercial toothpaste compositioncomprising stannous fluoride and zinc lactate. Results are determined bysample luminescence on a PerkinElmer 2104 EnVision Multilabel Reader.Luminescence is measured in units of cps (counts per second). Theresults are shown in Table 4 below.

TABLE 4 Sample Dilution Test Comp. 1:4 1:8 Comparative Ex. I 30,45458,334 Composition 1 10,982 15,808 Composition 2 9580 15,338 Composition4 8076 20,634 Composition 7 10,140 21,630

The results show that each of the Compositions of the invention inhibitbacterial growth much more effectively than the comparativecompositions.

The formulation of Comparative Example I is shown in table 5 below.

TABLE 5 Ingredient % w/w Comp. Ex. I Water and minors 9.50 (color,flavor) Stannous fluoride  0.454 Zinc lactate 2.50 Zinc phosphate —Thickeners 3.15 Glycerin 34.65  Abrasive silica 20.00  Sodium 13.00 Hexametaphosphate Propylene Glycol 7.00 Trisodium Citrate — DihydrateSodium — Tripolyphosphate Polyethylene Glycol 7.00 600 Tetrasodium —Pyrophosphate Anionic Surfactant 1.00 Trisodium Phosphate 1.10Zwitterionic — Surfactant Sodium Gluconate 0.65 Anionic Polymer — CitricAcid —

Example 4 Comparative Stability Study

A 13-week stability study is performed with two arms, one at roomtemperature and one at 40° C. Formulation A-1 is a dentifrice containing0.454% stannous fluoride, 1% zinc phosphate, 1.2% citrate buffer, and 4%TSPP. Formulation B contains 0.454% stannous fluoride, 1% zinc oxide,1.2% citrate buffer, and 4% TSPP. The results are shown in Table 6below.

TABLE 6 Soluble Fluoride (ppm) Soluble Tin (wt %) Soluble Zinc (wt %) 8weeks 13 Weeks 8 weeks 13 Weeks 8 weeks 13 Weeks Initial RT 40° C.Initial RT 40° C. Initial RT 40° C. Form. 1099 1080 1011 0.27 0.26 0.200.33 0.36 0.29 A-1 Form. 1124 1138 1136 0.07 0.00 0.00 0.44 0.32 0.22 BThe results demonstrate that while the use of zinc oxide results incomparable fluoride stability to using zinc phosphate, the solublestannous level and soluble zine level is significantly reduced bothinitially and over the course of the study when zinc oxide is usedinstead of zinc phosphate. This demonstrates that zinc phosphate has theability to stabilize stannous ion against oxidative degradation, whereaszinc oxide does not. Without being bound by theory, it is believed thatin the presence of citrate buffer, zinc oxide is solubilized andinteracts with stannous fluoride to cause conversion of the stannous ionto stannous hydroxide, which precipitates out. In contrast, zincphosphate is able to maintain zinc and stannous in a bioavailablesoluble form in the presence of citrate buffer.

Example 5 Comparative Stability Study

An additional stability study is performed in which the soluble tinrecoverable is compared between a formulation according to the presentinvention (Formulation A-2) and two commercial competitors (ComparativeB and C). The study is performed for 13 weeks at room temperature.Formulation A-2 comprises 0.454% stannous fluoride, 1% zinc phosphate,1.2% citrate buffer, and 2% TSPP (Formula A-2 is essentially the same asFormulation A-1, except that it contains 2% TSPP instead of 4% TSPP).Comparative composition B is a low water composition comprising 0.454%stannous fluoride, about 2.5% zinc lactate, and about 10% water.Comparative composition C is a high-water composition comprising 0.454%stannous fluoride, 0.27% stannous chloride, 0.5% zinc citrate, and about43% water. The results shown in Table 7 below demonstrate that whileexisting low-water stannous fluoride compositions can achieve stannousion stability, high water compositions cannot. Indeed, the commercialformulation comprising more than double the total tin salt contentresults in half as much recoverable soluble tin at the conclusion of thestudy.

TABLE 7 Total Soluble Tin at Added Tin 13 Weeks (wt %) (wt %)Formulation A-2 0.34 0.22 Comparative B 0.34 0.20 (low water)Comparative C 0.72 0.10 (high water)

Example 6 Quantification of Soluble Tin (II) by Titration with Iodine

Tin can exist in two oxidation states, Sn(II) (stannous) and Sn(IV)(stannic). Oxidizing agents, including atmospheric oxygen, can oxidizeSn(II) to Sn(IV). Soluble Sn(II) can be rapidly quantified by titratingwith the inorganic oxidizing agent iodine, such as according to themethod of Howe, P., and Watts, P., Tin and inorganic tin compounds,(World Health Organization, 2005). Formulation A-2, and ComparativeFormulations B and C, as described above, are tested for soluble tinusing this method. The results are shown in Table 8 below. These resultsfurther demonstrate that a composition according to the inventionunexpectedly stabilizes tin in a high water composition.

TABLE 8 Tin (II) (Wt %) Formulation A-2 0.25 Comparative B 0.13 (lowwater) Comparative C 0.16 (high water)

Example 7 Comparative Antibacterial Efficacy

The antibacterial efficacy of Formulation A-2 is compared to variouscommercial competitor formulations using the planktonic bacteria ATPluminescence assay described in Example 3. Formulation A-2 is adentifrice comprising 0.454% stannous fluoride, 1% zinc phosphate, 1.2%citrate buffer, and 2% TSPP. Comparative composition C is a high-watercomposition comprising 0.454% stannous fluoride, 0.27% stannouschloride, 0.5% zinc citrate, and about 43% water. ComparativeComposition D is a commercial stabilized stannous dentifrice comprisingabout 0.45% stannous fluoride in a substantially anhydrous (zero-water)base. The results are shown in Table 9 below. Samples are diluted 1:8 ina mixture of saliva and PBS. Positive controls are measured for salivaalone and the saliva/PBS mixture used for sample dilution. The resultsshow that Formulation A-2 is significantly more effective in killingbacteria compared to any of the commercial competitors.

TABLE 9 Luminescence (cps) Saliva (Control) 168398 Saliva/PBS 109810(Control) Formulation A-2 4954 Comparative C 65192 (high water)Comparative D 11612 (no water)

Example 8 Enamel Protection

Four commercial toothpaste compositions are compared to Formulation A-2in a 5% citric acid etching and post pH cycling experiment. ComparativeCompositions B, C and D, are as described above. Comparative compositionE is a standard commercial sodium fluoride toothpaste without zinc orstannous agents. Bovine enamel substrates (N=10 per cell) were preparedby embedding bovine incisors in methacrylate resin blocks, and polishingconsecutively with 600 and 1200 grit carbide paper. Care is taken not topenetrate the dentin layer while polishing the enamel to a mirrorfinish. Prior to testing, each enamel substrate is pre-etched by30-seconds of treatment with 5% citric acid. Half of each enamel core isprotected with acid-resistant tape to serve as a negative control. Themicrohardness is measured as a baseline for further testing. The modeluses involves six cycles repeated consecutively, wherein each cyclecomprises 1 hour of storage of the enamel substrate at 37° C. in saliva,followed by a ten-second rinse, followed by either 1 minute of treatmentor 2 minutes of acid challenge, followed by a ten second rinse. Thecycle repeats a total of six times. In the first and sixth cycles, atreatment step is used, while in the second through fifth cycles, acidchallenge is applied. After the final step, the enamel cores are storedovernight in saliva at 37° C. Thus, the daily sequence can be summarizedas T-C-C-C-C-T (T=treatment; C=acid challenge). The entire processrepeats for five consecutive days. Each acid challenge step involvestreatment with a 1% aqueous citric acid solution adjusted to pH 3.8. Atthe conclusion of the 5-day study, microhardness is evaluated bycomparison to the control side of each enamel core. The percent changein hardness is calculated.

The results are presented in Table 10 below. The results show thatFormulation A-2 provides unexpectedly better enamel protection comparedto each of the comparative commercial compositions.

TABLE 10 % Mineral Loss Formulation A-2 45 Comparative B 50 (low water)Comparative C 49 (high water) Comparative D 52 (no water) Comparative E57 (sodium fluoride)

Example 9 Optimization of Phosphate and Citrate

Chelating systems are well known for increasing analytical availability(recovery) of metal ions, such as stannous and zinc. However,over-chelation can decrease bioavailability, and therefore can alsodecrease anti-bacterial efficacy. Both organic acids, such as citricacid and citrate salts, and polyphosphates, such as pyrophosphates andtripolyphosphates, are capable of chelating divalent metal ions, such asstannous and zinc. To evaluate the optimization of polyphosphate andcitrate concentrations, a series of aqueous test solutions are preparedand analyzed for soluble stannous concentration, stannous ion uptake andstannous bioavailability.

Solutions are prepared comprising 1.7 wt % zinc phosphate, 0.454 wt %stannous fluoride, and varying amounts of tetrasodium pyrophosphate(TSPP) and citrate buffer (1:5 citric acid to trisodium citrate) in a2:1 v/v mixture of sorbitol and water. Samples are shaken to disperseand pH adjusted to 6.5. Each solution is then centrifuged at 10,000 rpmfor 10 minutes to remove any suspended particles and then thesupernatant is submitted to analysis.

Paraffin-stimulated whole saliva is collected from healthy male orfemale subjects. Saliva supernatant is obtained by centrifuging wholesaliva for 10 minutes at 7500 g. Bovine enamel blocks are incubatedovernight at 37° C. in 1 mL of saliva in order to develop a pellicle.Samples are prepared in triplicate. Each set is treated with 5 mL of 1%aqueous citric acid for 2 minutes, and then rinsed with deionized water.Following rinsing, each block is treated with 5 mL of the test solutionwith shaking for 2 minutes at 37° C.) Each set is then rinsed withdeionized water, and individual bovine blocks are placed into separatevials. All blocks are then treated with 10 mL of freshly prepared 6%aqueous citric acid for one hour. The acidic solution is then removedinto new tubes and submitted to analysis. The results are shown in Table11 below. For comparison of the results, the bioavailability ofexperiment 4 is set to 100%.

TABLE 11 Citrate Sn % Bio- TSPP Buffer % Soluble Uptake available # (wt%) (wt %) pH Sn (ppm) Sn 1 0 0 6.1 0 — — 2 4 4 6.8 0.37 1.22 38% 3 01.41 6.5 0.35 2.18 67% 4 1.58 1.23 6.1 0.39 3.23 100%  5 1.06 0 6.5 0.372.97 92%

The results demonstrate that in the absence of chelating agent, there isno recovery of soluble stannous ion. The results also show that optimalstannous ion uptake is achieved by using a mixture of TSPP and citratebuffer, but also that over-inclusion of these chelating agents (4% ofeach) results in over-chelation and a consequent decrease in uptake andbioavailability (despite a high soluble stannous concentration).

While the present invention has been described with reference toembodiments, it will be understood by those skilled in the art thatvarious modifications and variations may be made therein withoutdeparting from the scope of the present invention as defined by theappended claims.

The invention claimed is:
 1. A high water oral care composition comprising an orally acceptable carrier, zinc phosphate, stannous fluoride, tetrasodium pyrophosphate or tetrapotassium pyrophosphate, abrasive, and a citrate buffer system, wherein the stannous fluoride is from 0.01% to 5% by weight, relative to the weight of the oral care composition; wherein the amount of zinc phosphate is present in an amount of from 0.5 to 4% by weight, relative to the weight of the oral care composition, wherein the buffer system comprises citric acid and trisodium citrate, wherein the buffer system is in an amount of 1.2%, by weight of the composition; wherein the buffer system comprises citric acid and the trisodium citrate salt, in a weight ratio of from 1:3 to 1:6; and wherein the amount of water is from 10%-30% by wt, relative to the weight of the oral care composition.
 2. A composition according to claim 1, wherein the zinc phosphate is a preformed salt of zinc phosphate.
 3. A composition according to claim 1, further comprising one or more humectants.
 4. A composition according to claim 1, further comprising one or more surfactants.
 5. A composition according to claim 1, further comprising one or more sources of zinc ions in addition to the zinc phosphate, selected from zinc citrate, zinc oxide, zinc lactate, zinc pyrophosphate, zinc sulfate, and zinc chloride.
 6. A composition according to claim 1, wherein the oral care composition is a dentifrice, powder, cream, strip or gum.
 7. A method of treatment or prevention of erosive tooth demineralization, gingivitis, plaque, and/or dental caries, the method comprising the application to the oral cavity of a person in need thereof a composition according to claim
 1. 8. The method of claim 7, wherein the method is effective to (i) reduce or inhibit formation of dental caries, (ii) reduce, repair or inhibit pre-carious lesions of the enamel, (iii) reduce or inhibit demineralization and promote remineralization of the teeth, (iv) reduce hypersensitivity of the teeth, (v) reduce or inhibit gingivitis, (vi) promote healing of sores or cuts in the mouth, (vii) reduce levels of acid producing bacteria, (viii) to increase relative levels of arginolytic bacteria, (ix) inhibit microbial biofilm formation in the oral cavity, (x) raise and/or maintain plaque pH at levels of at least pH 5.5 following sugar challenge, (xi) reduce plaque accumulation, (xii) treat, relieve or reduce dry mouth, (xiii) clean the teeth and oral cavity (xiv) reduce erosion, (xv) prevents stains and/or whiten teeth, (xvi) immunize the teeth against cariogenic bacteria; and/or (xvii) promote systemic health, including cardiovascular health. 